Broad-spectrum antimicrobial compositions based on combinations of taurolidine and protamine and medical devices containing such compositions

ABSTRACT

Novel antimicrobial compositions and coatings are disclosed. The antimicrobial compositions consist of mixtures of taurolidine and protamine, including protamine salts. The antimicrobial compositions are particularly useful in coatings for implantable medical devices. The antimicrobial compositions are effective against a broad spectrum of microbes.

FIELD OF THE INVENTION

The field of art to which this invention relates is antimicrobialcompositions, more specifically combinations of taurolidine andprotamine for use with medical devices.

BACKGROUND OF THE INVENTION

Hospital acquired infections are of great concern to health careproviders and patients. Relatively routine surgical procedures can havedisastrous health consequences when a patient acquires an infection atthe surgical site, even though the underlying surgical procedure wassuccessful. Hospitals and health care providers have institutedinfection control and prevention protocols and precautions to reduce theincidence of hospital acquired infections. These include sterile fieldsin the operating room, instrument sterilization procedures, gowning andgloves, HEPA filtered air streams, antimicrobial wipedowns of thepatient's skin surrounding the surgical site prior to initiating theprocedure, cleaning protocols, etc. However, notwithstanding suchprocedures and protocols, whenever a medical device is used in asurgical setting, a risk of infection is created, even though themedical device itself is sterile as provided in its packaging. The riskof infection dramatically increases for invasive or implantable medicaldevices, such as intravenous catheters, arterial grafts, intrathecal orintracerebral shunts, meshes, sutures, sealants and prosthetic devices,which create a portal of entry for pathogens while in intimate contactwith body tissues and fluids. The occurrence of surgical site infectionsis often associated with bacteria that colonize on a medical device andform biofilms. For example, during a surgical procedure, bacteria fromthe surrounding environment may enter the otherwise sterile fieldsurrounding a surgical site and attach to a medical device that iseither in contact with the patient or implanted into the patient.Bacteria can then use the implanted medical device as a pathway tosurrounding tissue. Such bacterial colonization on the medical devicemay lead to an infection resulting in morbidity and mortality.

A number of methods for reducing the risk of infection associated withinvasive or implantable medical devices have been developed thatincorporate antimicrobial agents into or onto the medical devices, forexample, antimicrobial coatings or compounding polymeric materials withsuch agents. Such devices desirably provide suffiently effective levelsof antimicrobial agent to counteract any bacterial contamination thatmight have entered the patient for a period of time after the device isin place, including inhibiting the formation of difficult to treatbiofilms. Conventional antimicrobial compositions that have been usedwith implantable medical devices include triclosan, silver, andchlorhexidine gluconate, and may also include antibiotics such asrifampin, minocycline, clindamycin and gentamicin. However, it can beappreciated that the use of antibiotics for this purpose raises concernswith respect to antibiotic resistance. Such resistance is typically notpresent with antimicrobials that are not antibiotics.

Antimicrobial compositions for use in treating medical devices are knownin the art. The compositions may be applied to the devices viaconventional coating processes, or may be compounded into polymercompositions used to manufacture the devices. However, a distinction isdrawn between devices that are implanted into the body versus devicesthat may have limited contact with body tissue and bodily fluids. Thetoxicity of an efficacious antimicrobial composition which is usefulwith a device that is not designed for implantation may preclude the useof that antimicrobial in or on an implantable device. This is especiallytrue with large implants having correspondingly large surface areas.

One particular challenge with regard to making large-sized antimicrobialimplant devices, such as surgical meshes, relates to applying safe andeffective amounts of antimicrobial compositions sufficient to protectthe implant from bacterial colonization after implantation, whileproducing no harmful side effects to patients and retaining thefunctionality of the devices. Taurolidine is known to be a mildantibacterial agent with a history of safe internal (in vivo) use, andthus has the potential to be used safely with implantable medicaldevices. One challenge associated with using Taurolidine on, or in, animplantable medical device is the large quantity of the antimicrobialcomposition typically required in order to be efficacious. This mayaffect several functional aspects of the device, including theappearance (e.g., flecking) and handling (e.g., flexibility) of thedevice. In addition, large quantities of any antimicrobial may have sometoxic effects after implantation. The degree of toxicity is oftencorrelated with the quantity or amount of the antimicrobial present onor in the device.

The use of taurolidine is often associated with catheter or fluid locks.Protamine sulfate is also known to be used with such locks as ananticoagulant. Such uses do not contemplate long term implanted medicaldevices, since anticoagulants are often contraindicated for obviousreasons.

Therefore, there is a need for new and improved, safe and efficacious,antimicrobial compositions for use with implantable medical devices thathave improved antimicrobial performance while utilizing decreasedamounts of the compositions.

SUMMARY OF THE INVENTION

Accordingly, novel antimicrobial compositions are disclosed. Theantimicrobial compositions are useful with implantable medical devices.The compositions consist of about 50 wt. % to about 99 wt. % oftaurolidine and about 1 wt. % to about 50 wt. % of protamine or aprotamine salt.

Another aspect of the present invention is a medical device having atleast a section or portion of a surface coated with the above-describedantimicrobial composition. In a preferred embodiment, the medical deviceis implantable.

Yet another aspect of the present invention is an antimicrobial coatingcomposition containing the above-described antimicrobial composition.The coating composition is especially useful with implantable medicaldevices.

Still yet another aspect of the present invention is a method of coatingat least a section or portion of a surface of a medical device with theabove-described antimicrobial composition or antimicrobial coatingcomposition. The method is especially useful for implantable medicaldevices.

A further aspect of the present invention is a medical device made froma combination of a polymer resin and the above-described anti-microbialcomposition. In a preferred embodiment the devices are implantable.

These and other features and advantages of the present invention willbecome more apparent from the following description and accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the synergy of taurolidine and protaminesulfate by an in vitro efficacy assay against S. aureus.

FIG. 2 is a graph showing the synergy of taurolidine and protaminesulfate by an in vitro efficacy assay against E. coli

DETAILED DESCRIPTION OF THE INVENTION

The term implantable medical devices as used herein is defined to haveits conventional meaning and refers to any device or implant made from abiocompatible material for insertion or implantation into the body of ahuman or animal subject, including but not limited to stents (e.g.,coronary stents, vascular stents including peripheral stents and graftstents, urinary tract stents, urethral/prostatic stents, rectal stents,esophageal stents, biliary stents, and pancreatic stents), surgicalsutures, surgical needles, meshes, electrodes, catheters, leads,implantable pacemakers, cardioverter or defibrillator housings, joints,screws, rods, ophthalmic implants, femoral pins, bone plates, grafts,anastomotic devices, perivascular wraps, sutures, staples, shunts forhydrocephalus, dialysis grafts, colostomy bag attachment devices, eardrainage tubes, leads for pace makers and implantable cardioverters anddefibrillators, vertebral disks, bone pins, suture anchors, hemostaticbarriers, clamps, screws, plates, clips, vascular implants, tissueadhesives and sealants, tissue scaffolds, various types of dressings(e.g., wound dressings), bone substitutes, intraluminal devices,vascular supports, etc., and equivalents thereof.

The implantable medical devices may be formed from any suitableconventional biocompatible material, including but not limited topolymers (including stable or inert polymers, organic polymers,organic-inorganic copolymers, inorganic polymers, and biodegradablepolymers), metals, metal alloys, inorganic materials such as silicon,glasses, and composites thereof, including layered structures with acore of one material and one or more coatings of a different material.The materials may be bioabsorbable, partially bioabsorbable, ornonabsorbable. The term bioabsorbable as used herein is defined to haveits conventional meaning as being essentially a polymeric material thatis absorbed from the locus of implantation in less than three years.Wherein the bioabsorbable polymer may be biodegradable whereby thebackbone or sidechains degrade or dissolve into lower molecular weightpolymers that are metabolized and/or excreted from the body.

The bioabsorbable polymers may include conventional biocompatiblebioabsorbable polymers including, but not limited to, polyethers such aspolyethylene glycol or polyethyleneoxide, polyvinylpyrroldine,polyvinylalkohol, polyhydroxy acids, polylactides, polyglycolides,polyhydroxy butyrates, polyhydroxy valeriates, polycaprolactones,polydioxanones, synthetic and natural oligo- and polyamino acids,polyphosphazenes, polyanhydrides, polyorthoesters, polyoxaesters,polyphosphates, polyphosphonates, polyalcohols, polysaccharides,polyethers, polyamides, aliphatic polyesters, aromatic polyesters,copolymers of polymerizable substances thereof, and resorbablebioglasses. The nonabsorbable polymers may include conventionalbiocompatible polymers including, but not limited to, polyalkenes,polypropylene, polyethylene, partially halogenated polyolefins, whollyhalogenated polyolefins, fluorinated polyolefins,polytetrafluorethylene, polyvinylidene fluoride, polyisoprenes,polystyrenes, polysilicones, polycarbonates, polyarylether ketones,polymethacrylic acid esters, polyacrylic acid esters, polyimides, nondegradable polysaccharides such as cellulose, bacterial cellulose, andcopolymers of polymerizable substances thereof.

The components of the antimicrobial compositions of the presentinvention include a methylol-containing compound such as taurolidine andprotamine, or preferably a particular a protamine salt such as protaminesulfate or protamine hydrochloride, optionally in a solvent or coatingsolution.

By “methylol-containing compound,” or “methylol transfer agent,” ismeant a compound which contains or is capable of producing a methylolmolecule under physiological conditions. A methylol-containing compoundis characterized as having a R—CH2-OH group in which R is an alkyl, arylor hetero group. The invention also includes the use of compoundscapable of producing or being converted into a compound containing anR—CH2-OH structure.

Taurolidine (bis(1,1-dioxoperhydro-1,2,4-thiadiazinyl-4)-methane) is aderivative of the amino acid taurine and has antimicrobial properties.Taurolidine is believed to act via a chemical reaction with bacterialcell wall structures. Bacteria exposed to the compound are killed andreleased toxins are inactivated. Taurolidine has been shown to be safeand well tolerated at systemic doses exceeding 40 g/day and cumulativedoses up to and exceeding 300 g. Taurolidine has been used to treatpatients with peritonitis and used as a catheter lock solution for theprevention of central venous catheter-related infections. Compared toother known antimicrobial compositions used on medical devices, theantimicrobial properties of taurolidine are relatively weaker, thereforemore dosing is needed for efficacy. Even though the quantities oftaurolidine required to achieve efficacy on a particular medical devicemay be safe and biocompatible, the physical properties of a coating onthe medical device containing such a relatively high dose might beadversely impacted and affected. Therefore, a highly effectivecomposition having reduced amounts of the antimicrobial agent is neededfor taurolidine use on medical devices. Taurolidine-like compounds likeTaurultame (38668-01-8), Cyclotaurolidine (220928-22-3) or similaracting molecules like Cilag 61 (531-18-0) or Noxiflex S (15599-39-0) maybe used alternatively or in combination with taurolidine in the practiceof the present invention.

Protamine is a small arginine-rich, highly cationic peptide. Protaminewas discovered combined with nucleic acids in the sperm of certain fish,and has the property of neutralizing heparin. Protamine sulfate isusually administered to reverse a large dose of heparin administeredduring certain surgeries. Protamine may also be used in its free formand in the form of a salt. A suitable protamine useful in the practiceof the present invention is, for example, protamine sulfate or protaminehydrochloride. In the practice of the present invention it is preferredthat pharmagrade-approved protamine (USP grade) sources are used.

Protamine is also used as a mixture of peptides. According to Hvass(2005), Hvass A and Skelbaek-Pedersen B, J. Pharm Biomed Anal37(3):551-7 (2005), commercially available protamines are usuallyobtained as the sulphate salt, and for insulin formulations, salmineprotamine from fish of the family Salmonidae is normally used. Salmineprotamine may be classified as a mono-protamine as only one basic aminoacid, Arginine, is present. The four major peptides, which constitutealmost the entire nitrogen containing material in salmine protamine,have been fully characterized.

According to Block (1937), Yale J Biol Med. 1937 May; 9(5): 445-503, theprotamines have been divided into four groups depending on their contentof the major or basic amino acids; those containing(1) arginine only (monoprotamines)(2) arginine and lysine (diprotamines)(3) arginine and histidine (diprotamines)(4) arginine, histidine, and lysine (triprotamines)Examples of protamines and hydrolizates or fragments thereof that areuseful are described below.

-   -   Hydrolized protamine (1030905-03-3, Sequence: 1 RRRRGGRRRR)    -   Low Molecular Weight Protamine (121052-30-0, Sequence Length:        14, Sequence: 1 VSRRRRRRGG RRRR)    -   Low Molecular Weight Protamine (756860-86-3, Sequence Length: 6,        Sequence: 1 PRRRRR)    -   Low Molecular Weight Protamine (756860-88-5, Sequence Length:        13, Sequence: 1 ASRRRRRGGR RRR)    -   Low Molecular Weight Protamine (1115247-45-4, Sequence Length:        10, Sequence: 1 PRRRRSSPPR)    -   Stelline C (142847-28-7, Sequence Length: 26, Sequence: 1    -   RRRRRHASTK LKRRRRRRRH GKKSHK)    -   Protamine 1a (Oncorhynchus mykiss testis) (78473-81-1, Sequence        Length: 30, Sequence: 1 PRRRRASRRV RRRRRPRVSR RRRRGGRRRR)    -   Protamine (rat sperm reduced) (119370-87-5, Sequence Length: 50        Sequence: 1 ARYRCCRSKS RSRCRRRRRR CRRRRRRCCR RRRRRCCRRR        RSYTFRCKRY)    -   1 Protamine St 1 (horse sperm reduced) (110616-21-2, Sequence        Length: 49, Sequence: ARYRCCRSQS QSRCRRRRRR RCRRRRRRSV        RQRRVCCRRY TVLRCRRRR)    -   Protamine (Dicentrarchus labrax) (147414-03-7Sequence Length: 34    -   Sequence: 1 PRRRRQASRP VRRRRRTRRS TAERRRRRVV RRRR)    -   Ecmolin (8001-16-9) a Triprotamin    -   Additional Protamine-like molecules which are acting as        anti-heparin agents such as Polybrene, Terlipressin,        Romiplostim, Eltrombopag, or condensed DNA like Polyarginine,        Polylysin and finally protamine-like proteins or protamine-like        peptides which are a group of sperm nuclear basic proteins        (SNBPs) together with protamine type and histone type.        Protamine-like SNBPs represent the most structurally        heterogeneous group, consisting of basic proteins which are rich        in both lysine and arginine amino acids. Additional        protamine-like peptides are described sometimes according to        U.S. Pat. No. 5,614,494 as are synthetic protamine-like        polycationic peptides having a total cationic charge which is        less than that of n-protamine.    -   Additional Protamine like molecules can have the same mode of        action in the case of sustained insulin formulations like Surfen        (dihrochloride 5424-37-3 or base 3811-56-1), globin optional        with a trace of zink.

The amount of taurolidine and protamine in the antimicrobialcompositions of the present invention will be sufficient to provideeffective antimicrobial activity without exhibiting any significantlevels of toxicity. Typically the amount of taurolidine present in theantimicrobial compositions will be about 50 wt. % to about 99 wt. %,more typically about 60 wt. % to about 90 wt. %, and preferably about 70wt. % to about 90 wt. %. The amount of protamine or protomine saltpresent in the antimicrobial compositions will typically be about 1 wt.% to about 50 wt. %, more typically about 5 wt. % to about 50 wt. %, andpreferably about 10 wt. % to about 50 wt. %.

The antimicrobial compositions of the present invention may be utilizedwith medical devices to provide an antimicrobial effect in a variety ofways. The compositions may be included in coating compositions andcoated onto surfaces of medical devices using conventional coatingprocesses including dipping, brushing, and spraying. The antimicrobialcompositions may also be incorporated into medical devices in otherconventional manners, including compounding into a resin, and thenextruding or molding a medical device from the resulting compoundedresin.

Conventional techniques and processes may be used to apply thecompositions and coatings of the present invention onto the surfaces ofmedical devices and implants. The techniques include, but are notlimited to, dip coating, spraying, inkjet (solvent jet) application,swelling, powder coating with sintering, injection molding, and plasmaor laser deposition coating, etc. As mentioned previously above, ifdesired, the antimicrobial compositions of the present invention may becompounded or blended with polymeric materials, which are then used asmixtures or blends in solid or semi-solid form as granules or powders.Such polymeric mixtures or blends may then be processed in conventionalmanners including, but not limited to, compressed into tablets,extruded, injection molded, etc.

In one preferred embodiment, the antimicrobial coatings of the presentinvention are applied as liquid coating compositions. The liquid coatingcompositions will typically utilize one or more liquid solvents orcarriers, and depending upon the indication, different solvent systemsmay be used.

The conventional solvents that are optionally included in theantimicrobial coating compositions of the present invention include, butare not limited to, water for injection, ethanol/water mixtures,isopropanol water mixtures, glycerol/water mixtures, protein solutions,and blood and serum. If desired, additional conventional biocompatiblecomponents may be included in the antimicrobial compositions of thepresent invention when used as a coating composition includingsurfactants, thickeners, polyvinylpyrrolidones, polyethyleneglycols,carboxymethylcellulose, hydroxyethylstarch, hydroxypropyl starch,dextrane, polyoxypropylene-polyoxyethylene copolymers, polyethoxylatedcastor oils, etc., and combinations thereof. The antimicrobial coatingsof the present invention will contain a sufficient amount of theantimicrobial compositions of the present invention to provide aneffective antimicrobial effect without exhibiting significant levels oftoxicity. For example, the amount of the antimicrobial compositions ofthe present invention contained in the coating compositions willtypically be about 0.1 wt. % to about 10 wt. %, more typically about 2wt. % to about 4.5 wt. %, and preferably about 2 wt. %, with theremainder being solvent or solvents and other optional additives. Thoseskilled in the art will appreciate that these amounts may vary dependingupon several factors including the size and shape of the medical device,the location of the implanted device in the body, the composition of theimplanted device, the age and weight of the patient, the duration of thelength of time that the implant will remain in the patient's body, thesurface area of the implant, etc.

When using the antimicrobial compositions of the present invention in anantimicrobial coating composition, the coating compositions can beprepared in a conventional manner. For example, a required amount of theantimicrobial composition is admixed with solvent in a conventionalmixing vessel in the following manner. A suitable, conventional vesselis provided with a stirring device such as a magnet stirring bar or apaddle stirrer. A solvent or solvent mixture is added to the vessel anda defined amount of protamine or protamine salt such as protaminesulfate is added to the vessel under stirring. The mixture is warmed ifor as needed, and a defined amount of taurolidine is added. Anyadditional solvent/solvent mixture as needed is added to adjust thefinal concentration of said mixture. Those skilled in the art willappreciate that additional conventional biocompatible components may beadded to the coating compositions including resins, surfactants,pigments, etc.

For injection or internal use such as intraperitoneal lavage basicallywater-based systems are preferred, e.g., Ringer, isotonic NaCl orGlucose. The pH can be adjusted with HCl, H2SO4 or Phosphoric acid for apH of 5-7. Viscosity enhancers such as PVP, HES or CMC may be optionallyadded. Acceptable injectable preserving agents such asmethyl-4-hydroxybenzoate or propyl-4-hydroxybenzoate can also be added.Such solutions might be also used to treat an implantable medical devicejust before use by dipping or washing or rinsing.

Depending upon the indication, dispersions of one or more compoundsmight be used. Heparin/Protamine particles could prepared according toMori (2010) in the presence of taurolidine or by adding tauroldine in aseparate step, Mori et al. (2010), Mori Y, Nakamura S, Kishimoto S,Kawakami M, Suzuki S, Matsui T, Ishihara M, International Journal ofNanomedicine Vol 5, 147-155 (2010).

For topical application, a certain amount of alcohol such as, forexample ethanol or isopropanol, without inducing flocculation of theprotamine may be added, preferably below 40% (v/v) of the alcoholcomponent if a solution is needed. Otherwise water for injection,hydrochloric acid to adjust the pH, macrogol 4000 and NaCl arepreferred. Additional ingredients optionally include (3-amidopropylcocoate) dimethylammonium acetate, sodium D gluconate, glycerol 85%,sodium chloride, and purified water.

Protamine sulfate solution 1% is compatible in 1 to 9 to 1:1 ratios withLavasept concentrate (20% Polyhexanid and 1% Macrogol 4000) or withOctenisept. Taurolidine can be dissolved in the mixture to give a finalconcentration of 2% taurolidine.

In order to coat an implantable medical device before packaging toprovide a coated device of the present invention, several types ofcoating solutions may be utilized containing the antimicrobialcompositions of the present invention depending upon the desiredresults, coating processes, application, etc. A coating compositionwithout a binder or with a water soluble binder such as PVP, PEG, CMC,HES, Dextran, Pluronics, Chremophors can be utilized and made from amixture of taurolidine/protamine in water. If a coating concentrationgreater than 2% wt. % taurolidine is required, taurolidine can bedissolved in acetone/water 90/10-70/30 for up to 4% wt. % and then theimplant is initially coated with taurolidine. If a polymeric binder isdesired or required such as PLA or PLGA, the polymer may be additionallydissolved in the acetone/water mixture. In a second step the protaminesolution is coated basically from water. The coating steps might beswitched and an interim drying step might be added. The amount ofoptional polymeric binder used in the coating compositions will besufficient to provide effective release of the taurolidine andadditionally ensure sufficient mechanical stability during handling.

Compounding of the antimicrobial compositions of the present inventionwith resins may be performed whereby the ratio of taurolidine to bulkpolymer (e.g., polydioxanone) for a surgical mesh should be higher than30% wt. % to 70% wt. %, preferably higher than 50 wt. % to 50 wt. % drugto polymer to ensure a sufficient high release rate. For bone implants,higher polymer ratios might be used to ensure a slower release andprolonged action. A mixture of taurolidine/protamine is preferablycompounded with polydioxanone below 150° C. and preferably under aprotective gas atmosphere such as nitrogen or argon. The compound can betransformed into different shapes, including medical devices, usingconventional processes such as injection molding and extrusion, orapplied to a medical device by conventional processes such as gluing,stitching, knitting, melting, etc. One preferred formulation techniqueis according to EP1251794, incorporated by reference, in Example 16,where small balls are introduced into an implantable cord. 1 mm to 3 mmballs can be prepared either by compounding, by tableting orincorporating into capsules. The implant is preferably absorbable andmay be used, for example, as an alternate antibiotic-free form for theSeptopal Chain TM system for osteomyelitis.

In another embodiment of the present invention, the antimicrobialcompositions of the present invention are encapsulated between twofilms, which may have pores of appropriate sizes to contain theantimicrobial composition and ensure a sufficiently effective release.The antimicrobial compositions of the present invention may be containedin a fabric pouch made from absorbable polymers, preferred are woven ornon woven materials having tiny pores to prevent powdering out of thecontainment.

For some indications it is beneficial to optionally use additionalactive agents in combination with the antimicrobial compositions of thepresent invention. Selection and utilization of an active agent incombination with the compositions of the present invention depends uponthe desired benefit intended to be derived. For example, it may beadvantageous to provide an implant (either coated or compounded)comprising an antimicrobial composition according to the invention thathas at least one additional biologically active ingredient or agent,which can optionally be released locally after the implantation.Substances which are suitable as active agents may be naturallyoccurring or synthetic and include and are not limited to, for example,antibiotics, antimicrobials, antibacterials, antiseptics,chemotherapeutics, cytostatics, metastasis inhibitors, antidiabetics,antimycotics, gynaecological agents, urological agents, antiallergicagents, sexual hormones, sexual hormone inhibitors, haemostyptics,hormones, peptide-hormones, antidepressants, vitamins such as Vitamin C,antihistamines, naked DNA, plasmid DNA, cationic DNA complexes, RNA,cell constituents, vaccines, cells occurring naturally in the body orgenetically modified cells. The active agent may be present in anencapsulated form or in an adsorbed form. With such active agents, thepatient prognosis can be improved according to the application or atherapeutic effect can be achieved (e.g., better wound healing, orinflammation inhibition or reduction).

Preferred as active agents are conventional antibiotics that includesuch agents as gentamicin or ZEVTERA™ (ceftobiprole medocaril) brandantibiotic (available from Basilea Pharmaceutica Ltd., BaselSwitzerland). Most preferred is the use of highly effective, broad bandantimicrobials against different bacteria and yeast (even in thepresence of bodily fluids) such as octenidine, octenidinedihydrochloride (available as active ingredient in Octenisept®disinfectant from Schulke & Mayr, Norderstedt, Germany as),polyhexamethylene biguanide (PHMB) (available as active ingredient inLavasept® from Braun, Switzerland), triclosan, copper (Cu), silver (Ag),nanosilver, gold (Au), selenium (Se), gallium (Ga), N-chlorotaurine,alcohol based antiseptics such as Listerine(R) mouthwash, Nalpha-lauryl-L-arginine ethyl ester, ethyl-N-alpha-lauroyl-L-arginatehydrochloride, (LAE), myristamidopropyl dimethylamine (MAPD, availableas an active ingredient in SCHERCODINE™ M), oleamidopropyl dimethylamine(OAPD, available as an active ingredient in SCHERCODINE· O), andstearamidopropyl dimethylamine (SAPD, available as an active ingredientin SCHERCODINE™ S), and most preferably octenidine dihydrochloride(hereinafter referred to as octenidine) and PHMB.

The amounts of the optional active agents that may be present in theantimicrobial compositions of the present invention will be sufficientto effectively provide additional inhibition of bacterial colonization,biofilm formation thus reduce the risk of infection.

Additionally, a conventional contrast agent may optionally beincorporated into the antimicrobial compositions or antimicrobialcoatings of the present invention. Such a contrast agent may be abiocompatible dye to create a visual marker as described in theEP1392198B1 or an agent such as a gas or gas creating substance forultrasound contrast or MRI contrast, such as metal complexes like GdDTPAor superparamagnetic nanoparticles (Resovist™ or Endorem™) as taught inthe EP 1324783 B 1. X-Ray visible substances (radiopaque) may optionallybe included as shown in the EP1251794B 1 including pure zirconiumdioxide, stabilized zirconium dioxide, zirconium nitride, zirconiumcarbide, tantalum, tantalum pentoxide, barium sulphate, silver, silveriodide, gold, platinum, palladium, iridium, copper, ferric oxides, notvery magnetic implant steels, non-magnetic implant steels, titanium,alkali iodides, iodated aromatics, iodated aliphatics, iodatedoligomers, iodated polymers, alloys of substances thereof capable ofbeing alloyed, and the like.

The following examples are illustrative of the principles and practiceof the present invention, although not limited thereto.

Example 1 Synergistic Mixture of Taurolidine+Protamine Sulfate on aPoly-g-Caprone Film Containing Hernia Mesh

A poly-g-caprone film laminate mesh comparable to Ethicon's PhysioMeshhernia mesh product (available from Ethicon, Inc, Somerville, N.J. USA)but without a marker was prepared and punched out into 1.5 cm disks.

Taurolidine was dissolved at 4% wt./vol. in a 70% acetone 30% watervol./vol. mixture. Protamine sulfate was dissolved at 10% wt./vol. inwater under warming. 50 μl of the taurolidine (TU) solution and 20 μl ofthe protamine (PS) solution were applied to each mesh disk using apipette and allowed to dry at 50° C. until the majority of the liquidwas gone and then stored under vacuum. First the taurolidine solutionwas applied, and then immediately thereafter the protamine sulfatesolution was applied. The in vitro bacteria attachment assay wasdeveloped for its utility of indicating biofilm prevention potential ofprototype mesh. Since bacterial attachment to a surface is the firststep of biofilm formation, a surface treatment that inhibits bacterialattachment would reduce the chance of subsequent biofilm formation. Theassay was conducted in SST (Serum Saline TSB) medium to mimic in vivoand clinical conditions. The formulation of SST is Tryptic Soy Broth(TSB):serum:saline in the ratio of 1:2:7. Each test article wasincubated in SST inoculated with Staphylococcus aureus ACTT 6538 orEscherichia coli ATCC 25922 at about 6 Log CFU/ml. After incubation withrotation of 60 rpm for 4 hours at 37° C., the mesh discs were washed insaline 3 times to remove unattached bacteria. Bacteria attached to themesh were collected by sonication in saline with neutralizing agent.Viable bacteria populations were measured by plate count on TSA (TrypticSoy agar) medium contain neutralizing agents. The use of neutralizingagents in bacteria suspension and plate count medium was to eliminateany carry over antimicrobial effect from the coating. The plates wereincubated at 37° C. for 24 hours. The number of attached viable bacteriawas reported as CFU/disc.

The data in Table 1 indicated that mesh surfaces treated with thecombination of TU and PS completely inhibited the attachment by S.aureus and E. coli in a serum containing media, while mesh surfacestreated with TU alone at the same dosage showed less inhibition than thecombination.

TABLE 1 Viable Bacteria Attached to a Surgical Mesh (EthiconPhysioMesh ® available from Ethicon, Inc.) Disc d = 1.5 cm after FourHour Incubation in Bacteria/Serum Broth (pH = 7.4). TU PS CFU/discCFU/disc Sample (mg/disc) (mg/disc) S. aureus E.coli AB596 2 0 100 500AB597 2 2 0 0 AB585 0 0 100,000 1,000,000 (Control) CFU: Colony formingunit

Example 2 Synergistic Bactericidal Composition of Taurolidine withProtamine Sulfate in Serum-Containing Medium (SST)

Concentration gradients of TU and PS were diluted in an SST medium andmade into a two-dimensional matrix. Bacteria of interest were inoculatedto the matrix at about 10e6 CFU/ml. S. aureus ACTT 6538 or E. coli ATCC25922 were used for this Example 2. After incubation at 37° C. for 24hours, viable bacteria populations were measured by plate count. Logreduction (LR) was used as the end point for efficacy and was definedas: Log CFU/ml of untreated control−Log CFU/ml of treated. Synergisticindex (SI) was defined as LR of a given combination−sum of LR of singlecomponent at the same concentration as in the combination. SI=0indicated additive effect, SI=1, indicated 90% more bacterial cedality,SI=2 indicated 99% more bacterial cedality, SI=3, indicated 99.9% morebacterial cedality, etc., by combination than its stand alonecompositions at the same usage, thus synergy.

A significant synergy was observed for the combination of protaminesulfate (PS) with taurolidine (TU) in serum-containing medium. When usedalone, TU at 100 ppm showed no efficacy (LR=0) and PS at 10 ppm showedsome efficacy (LR=3.5) against S. aureus. When combined 10 ppm PS with50 ppm or 100 ppm TU, significant efficacy of 6 log reduction wasachieved, as seen in the graph of FIG. 1. Also, a highly synergisticeffect was shown for the mixture of TU+PS against E. coli, as seen inthe graph of FIG. 2.

Example 3 In Vitro Efficacy of Surgical Implant Coated withTaurolidine+Protamine Sulfate

In accordance with Example 1, surgical mesh discs coated with differentstand alone and combinations of taurolidine+protamine sulfate wereprepared. Protocols of mesh coating and in vitro attachment assay as inExample 1 were used for this Example 3. The data is presented in Table2.

TABLE 2 Bacterial Attachment (S. aureus) onto Composite Meshes Coatedwith Taurolidine or Mixtures of Taurolidine + Protamine Sulfate after 4Hours in SST Medium at 37° C. Log Added log Synergistic TU/disc PS/discreduction reduction* index (SI)  500 μg — 1 — 50 μg 0.4  500 μg 50 μg1.5 1.4 ~0.1 1000 μg — 0.8 1000 μg 50 μg >6 1.2 >4.8 2000 μg — 2 2000 μg50 μg >6 2.4 >3.6 *The sum of log reduction of stand alone PS + logreduction of TU # Synergistic index (SI) was defined as LR of a givencombination - sum of LR of single component at the same concentration asin the combination. SI = 0 indicated additive effect, SI = 1, indicated90% more bacterial cedality, SI = 2 indicated 99% more bacterialcedality, SI = 3, indicated 99.9% more bacterial cedality by combinationthan its stand alone composition at the same usage thus synergy.The data in Table 2 showed a mild onset of a synergistic effect at a lowTU dose of 0.5 mg/disc, the synergy is pronounced at higher loadings of1.0 mg or 2 mg TU with 50 μg PS. An LR>6 and SI>3 at 1 mg and 2 mg TUplus 50 mg PS indicated that the combination completely inhibited S.aureus attached to the surface and the efficacy was shown to be >99.9%more than the sum of stand-alone efficacy.

Example 4 Synergistic Ratio of Protamine Sulfate (PS) and Taurolidine(TU)

The range of the ratios of the components of the synergisticantimicrobial compositions of the present invention was obtained by anin vitro MBC (minimum bactericidal concentration) study. The study wasconducted in SST medium inoculated with about 10⁶CFU/ml Staphylococcusaureus ACTT 6538. In vitro efficacy was evaluated for different ratiosof PS and TU combinations along with the stand alone (i.e., individual)compositions at the same concentrations as in the combinationcomposition. After incubation at 37° C. for 24 hours, viable bacteriapopulations were measured by plate count. Log reduction (LR) was used asthe end point for efficacy and was defined as Log CFU/ml of untreatedcontrol−Log CFU/ml of treated. The synergistic index (SI) was defined asthe LR of a given combination−sum of LR of single component at the sameconcentration as in the combination. An SI=0 indicated additive effect,SI=1, indicated 90% more bacterial cedality, SI=2 indicated 99% morebacterial cedality, SI=3, indicated 99.9% more bacterial cedality, etc.,by a combination than its stand alone components at the same usage, thussynergy.

The data for this testing is presented in Table 3 and showed thatsynergistic combinations of PS and TU was in the range of 1:1 to 1:100.Ratios of TU and PS outside this range showed no synergy or less thanits stand alone controls.

TABLE 3 In vitro Efficacy against S. Aureus by Log Reduction PS:TU LR-Added Synergy (w/w) LR-PS LR-TU combination efficacy index 50:1  3.1 02.9 3.1 −0.2 10:1  3.1 0 2.7 3.1 −0.4 1:1 3.1 0 4.5 3.1 1.4  1:10 0 0 60 6  1:50 0 0 4.7 0 4.7  1:100 0 0 1.3 0 1.3  1:200 0 0 0 0 0

A biofilm is an accumulation of microorganisms embedded in apolysaccharide matrix and adherent to a solid surface. Biofilms areclinically important, accounting for about eighty percent of hospitalacquired infections. Biofilms are known to be extremely resistant toboth immunological and antibiotic therapy. Microbial biofilms developwhen microorganisms irreversibly adhere to a surface and produceextracellular polymers that facilitate adhesion and provide a structuralmatrix. The matured matrix is highly functional to protect microrganismsfrom adverse conditions while continually dispersing free cells tospread and colonize new surfaces. Therefore, inhibiting adhesion ofbacteria to surfaces is important.

A medical device such as a mesh having an effective antimicrobialcoating would effectively inhibit bacterial attachment to the surfacesof the devices, thus preventing or substantially inhibiting biofilmformation. The data in Examples 1 and 3 demonstrated the effectivenessof a synergistic composition of the present invention against bacteriaattachment to a mesh prototype in a serum-containing medium. The datasuggests promising benefits of using the synergistic composition toprotect a medical device against biofilm formation.

The antimicrobial compositions of the present invention and medicaldevices coated with or containing such compositions have manyadvantages. The advantages include providing a synergistic antimicrobialcomposition with improved efficacy along with reduced usage. The reducedusage increases the safety margin, improves biocompatibility, improvesphysical device characteristics, and reduces material costs. A broaderspectrum provided by the compositions of the present invention resultsin the compositions being an effective treatment against a wide range ofmicroorganisms. The compositions of the present invention effectivelyinhibit bacteria attachment to surfaces of medical devices and help toprevent biofilm formation and related infections. There is no knownbacterial resistance to taurolidine, and it is non-antibiotic. Inaddition, the compositions of the present invention are non-toxic, andapproved for internal use.

Although this invention has been shown and described with respect todetailed embodiments thereof, it will be understood by those skilled inthe art that various changes in form and detail thereof may be madewithout departing from the spirit and scope of the claimed invention.

1. An antimicrobial composition, comprising: about 50 wt. % to about 99wt. % of taurolidine; and, about 1 wt. % to about 50 wt. % of protamine.2. The composition of claim 1, wherein the protamine comprises aprotamine salt.
 3. The composition of claim 2, wherein the protaminesalt is selected from the group consisting of protamine sulfate andprotamine hydrochloride.
 4. The composition of claim 3, wherein theprotamine salt comprises protamine sulfate.
 5. The composition of claim1, additionally comprising a solvent.
 6. The composition of claim 5,wherein the solvent is selected from the group consisting of water,water/ethanol, and water/isopropanol.
 7. The antimicrobial compositionof claim 1, comprising: about 70 wt. % to about 90 wt. % of taurolidine;and, about 10 wt. % to about 30 wt. % of protamine.
 8. The compositionof claim 7, wherein the protomine comprises a protamine salt.
 9. Thecomposition of claim 8, wherein the protamine salt is selected from thegroup consisting of protamine sulfate and protamine hydrochloride. 10.The composition of claim 9, wherein the protamine salt comprisesprotamine sulfate.
 11. The antimicrobial composition of claim 1,additionally comprising an antibiotic.
 12. The antimicrobial compositionof claim 11, wherein the antibiotic is selected from the groupconsisting of aminoglycosides, carbapenems, cephalosporinsglycopeptides, macrolides, lincosamides, penicillins, polypeptides,quinolones and tetracyclines.
 13. The composition of claim 12, whereinthe antibiotic is selected from the group consisting of (gentamicin),imipenem, cefazolin, vancomycin, erythromycin, clindamycin, ampicillin,polymyxin B, levofloxacin and minocycline.
 14. The antimicrobialcomposition of claim 1, additionally comprising an antimicrobial agentselected from the group consisting of taurultame, cyclotaurolidine,Cilag 61 and Noxiflex S.
 15. An antimicrobial coating composition formedical devices, comprising: an antimicrobial composition comprising:about 50 wt. % to about 99 wt. % of taurolidine, and about 1 wt. % toabout 50 wt. % of protamine: and, a solvent.
 16. The antimicrobialcoating composition of claim 15, wherein the solvent is selected fromthe group consisting of water, water/ethanol, and water/isopropanol. 17.The coating composition of claim 15, wherein the protamine comprises aprotamine salt.
 18. The coating composition of claim 17, wherein theprotamine salt is selected from the group consisting of protaminesulfate and protamine hydrochloride.
 19. The composition of claim 18,wherein the protamine salt comprises protamine sulfate.
 20. Theantimicrobial coating composition of claim 8, wherein the antimicrobialcomposition comprises: about 70 wt. % to about 90 wt. % of taurolidine;and, about 10 wt. % to about 30 wt. % of protamine.
 21. The coatingcomposition of claim 20, wherein the protamine comprises a protaminesalt.
 22. The coating composition of claim 21, wherein the protaminesalt is selected from the group consisting of protamine sulfate andprotamine hydrochloride.
 23. The coating composition of claim 22,wherein the protamine salt comprises protamine sulfate.
 24. The coatingcomposition of claim 15, additionally comprising an antibiotic.
 25. Theantimicrobial coating composition of claim 24, wherein the antibiotic isselected from the group consisting of aminoglycosides, carbapenems,cephalosporins glycopeptides, macrolides, lincosamides, penicillins,polypeptides, quinolones and tetracyclines.
 26. The coating compositionof claim 26, wherein the antibiotic is selected from the groupconsisting of gentamicin, imipenem, cefazolin, vancomycin, erythromycin,clindamycin, ampicillin, polymyxin B, levofloxacin and minocycline. 27.The antimicrobial coating composition of claim 15, wherein theantimicrobial composition additionally comprises an antimicrobial agentselected from the group consisting of taurultame, cyclotaurolidine,Cilag 61 and Noxiflex S.
 28. The antimicrobial coating composition ofclaim 15 additionally comprising a polymeric binder.
 29. Theantimicrobial coating composition of claim 28, wherein the polymericbinder is selected from the group consisting selected from the groupconsisting of polyvinylpyrrolidones, polyethyleneglycols,carboxymethylcellulose, hydroxyethylstarch, hydroxypropyl starch,dextrane, polyoxypropylene-polyoxyethylene copolymers, polyethoxylatedcastor oils, polyhydroxy acids, polylactides, polyglycolides,polyhydroxy butyrates, polyhydroxy valeriates, polycaprolactones,polydioxanones, synthetic and natural oligo- and polyamino acids,polyphosphazenes, polyanhydrides, polyorthoesters, polyoxaesters,polyphosphates, polyphosphonates, polyalcohols, polysaccharides,polyethers, polyamides, aliphatic polyesters, aromatic polyesters,copolymers of polymerizable substances thereof, resorbable glasses,fibrin, collagen, albumin, non-degradable polymers, polyalkenes,polypropylene, polyethylene, partially halogenated polyolefins, whollyhalogenated polyolefins, fluorinated polyolefins,polytetrafluorethylene, polyvinylidene fluoride, polyisoprenes,polystyrenes, polysilicones, polycarbonates, polyarylether ketones,polymethacrylic acid esters, polyacrylic acid esters, polyimides, nondegradable polysaccharides such as cellulose, bacterial cellulose, andcopolymers of polymerizable substances thereof.
 30. A coated medicaldevice, comprising: a medical device having at least one surface: and,an antimicrobial coating on at least a part of said surface, wherein thecoating comprises: about 50 wt. % to about 99 wt. % of taurolidine; and,about 1 wt. % to about 55 wt. % of protamine.
 31. The coated medicaldevice of claim 30, wherein the device is selected from the groupconsisting of surgical sutures, surgical needles, meshes, catheters,staples, tacks, stents, tapes, clips, plates, screws, suture anchors,orthopedic implants, tissue engineering substrates, tissue repairfabrics, breast implant, surgical foams, pouches, heart valves, sewingrings, pace makers, and dressings.
 32. The medical device of claim 30,wherein the device comprises a material selected from the groupconsisting of polymers, metals, ceramics, composites, biomaterials, andcombinations thereof.
 33. The medical device of claim 30, wherein theprotamine comprises a protamine salt.
 34. The medical device of claim33, wherein the protamine salt is selected from the group consisting ofprotamine sulfate and protamine hydrochloride.
 35. The medical device ofclaim 34, wherein the protamine salt comprises protamine sulfate. 36.The coated medical device of claim 30, wherein the antimicrobial coatingcomprises: about 70 wt. % to about 90 wt. % of taurolidine; and, about10 wt. % to about 30 wt. % of protamine.
 37. The medical device of claim36, wherein the protamine comprises a protamine salt.
 38. The medicaldevice of claim 37, wherein the protamine salt is selected from thegroup consisting of protamine sulfate and protamine hydrochloride. 39.The medical device of claim 38, wherein the protamine salt comprisesprotamine sulfate.
 40. The coated medical device of claim 30, whereinthe antimicrobial coating additionally comprises an antibiotic.
 41. Thecoated medical device of claim 40 wherein the antibiotic is selectedfrom the group consisting of aminoglycosides, carbapenems,cephalosporins glycopeptides, macrolides, lincosamides, penicillins,polypeptides, quinolones and tetracyclines.
 42. The coated medicaldevice of claim 41, wherein the antibiotic is selected from the groupconsisting of gentamicin, imipenem, cefazolin, vancomycin, erythromycin,clindamycin, ampicillin, polymyxin B, levofloxacin and minocycline. 43.The coated medical device of claim 30, wherein the antimicrobial coatingadditionally comprises an antimicrobial agent selected from the groupconsisting of taurultame, cyclotaurolidine, Cilag 61 and Noxiflex S. 44.The coated medical device of claim 30, wherein the antimicrobial coatingadditionally comprises a polymeric binder.
 45. The coated medical deviceof claim 44 wherein the polymeric binder is selected from the groupconsisting of polyvinylpyrrolidones, polyethyleneglycols,carboxymethylcellulose, hydroxyethylelstarch, hydroxypropyl starch,dextrane, polyoxypropylene-polyoxyethylene copolymers, polyethoxylatedcastor oils polyhydroxy acids, polylactides, polyglycolides, polyhydroxybutyrates, polyhydroxy valeriates, polycaprolactones, polydioxanones,synthetic and natural oligo- and polyamino acids, polyphosphazenes,polyanhydrides, polyorthoesters, polyoxaesters, polyphosphates,polyphosphonates, polyalcohols, polysaccharides, polyethers, polyamides,aliphatic polyesters, aromatic polyesters, copolymers of polymerizablesubstances thereof, resorbable glasses, fibrin, collagen, albumin,non-degradable polymers, polyalkenes, polypropylene, polyethylene,partially halogenated polyolefins, wholly halogenated polyolefins,fluorinated polyolefins, polytetrafluorethylene, polyvinylidenefluoride, polyisoprenes, polystyrenes, polysilicones, polycarbonates,polyarylether ketones, polymethacrylic acid esters, polyacrylic acidesters, polyimides, non degradable polysaccharides such as Cellulose,bacterial cellulose, and copolymers of polymerizable substances thereof.46. A method of coating a medical device, comprising the steps of:providing a medical device having at least one surface; and, coating atleast a section of the surface with an antimicrobial coatingcomposition, wherein the coating comprises: about 50 wt. % to about 99wt. % of taurolidine; and, about 1 wt. % to about 50 wt. % of protamine.47. The method of claim 46, wherein the protamine comprises a protaminesalt.
 48. The method of claim 47, wherein the protamine salt is selectedfrom the group consisting of protamine sulfate and protaminehydrochloride.
 49. The method of claim 48, wherein the protamine saltcomprises protamine sulfate.
 50. The method of claim 46, wherein thecoating additionally comprises a solvent.
 51. The method of claim 50,wherein the solvent is selected from the group consisting of water,water, water/ethanol, and water/isopropanol.
 52. The method of claim 46,wherein the antimicrobial coating composition comprises: about 70 wt. %to about 90 wt. % of taurolidine; and, about 10 wt. % to about 30 wt. %of protamine.
 53. The method of claim 52, wherein the protaminecomprises a protamine salt.
 54. The method of claim 53, wherein theprotamine salt is selected from the group consisting of protaminesulfate and protamine hydrochloride.
 55. The method of claim 52, whereinthe protamine salt comprises protamine sulfate.
 56. The method of claim46, wherein the antimicrobial coating composition additionally containsan antibiotic.
 57. The method of claim 56, wherein the antibiotic isselected from the group consisting of aminoglycosides, carbapenems,cephalosporins glycopeptides, macrolides lincosamides penicillinspolypeptides quinolones and tetracyclines.
 58. The method of claim 57,aminoglycosides, carbapenems, cephalosporins glycopeptides, macrolides,lincosamides, penicillins, polypeptides, quinolones and tetracyclines.59. The method of claim 46 antimicrobial, wherein the antimicrobialcoating composition additionally comprises an antimicrobial agentselected from the group consisting of taurultame, cyclotaurolidine,Cilag 61 and Noxiflex S.
 60. The method of claim 46, wherein theantimicrobial coating composition additionally comprises a polymericbinder.
 61. The method of claim 60, wherein the polymeric binder isselected from the group consisting of polyvinylpyrrolidones,polyethyleneglycols, carboxymethylcellulose, hydroxyethylelstarch,hydroxypropyl starch, dextrane, polyoxypropylene-polyoxyethylenecopolymers, polyethoxylated castor oils; polyhydroxy acids,polylactides, polyglycolides, polyhydroxy butyrates, polyhydroxyvaleriates, polycaprolactones, polydioxanones, synthetic and naturaloligo- and polyamino acids, polyphosphazenes, polyanhydrides,polyorthoesters, polyoxaesters, polyphosphates, polyphosphonates,polyalcohols, polysaccharides, polyethers, polyamides, aliphaticpolyesters, aromatic polyesters, copolymers of polymerizable substancesthereof, resorbable glasses, fibrin, collagen, albumine, non-degradablepolymers, polyalkenes, polypropylene, polyethylene, partiallyhalogenated polyolefins, wholly halogenated polyolefins, fluorinatedpolyolefins, polytetrafluorethylene, polyvinylidene fluoride,polyisoprenes, polystyrenes, polysilicones, polycarbonates,polyarylether ketones, polymethacrylic acid esters, polyacrylic acidesters, polyimides, non degradable polysaccharides such as Cellulose,bacterial cellulose, and copolymers of polymerizable substances thereof.62. The method of claim 46, wherein the medical device is selected fromthe group consisting of surgical sutures, surgical needles, meshes,catheters, staples, tacks, stents, tapes, clips, plates, screws, sutureanchors, orthopedic implants, tissue engineering substrates, breastimplant, surgical foams, pouches, heart valves, sewing rings, pacemakers, and dressings.
 63. The method of claim 46, wherein the medicaldevice comprises a material selected from the group consisting ofpolymers, metals, ceramics, composites, biomaterials, and combinationsthereof.
 64. An antimicrobial composition, comprising: about 50 wt. % toabout 99 wt. % of at least one methylol-containing compound; and, about1 wt. % to about 50 wt. % of protamine.
 65. The composition of claim 64,wherein the methylol-containing compound is taurolidine.
 66. Theantimicrobial composition of claim 64, additionally comprising anantimicrobial agent selected from the group consisting of taurultame,cyclotaurolidine, Cilag 61 and Noxiflex S.
 67. The antimicrobialcomposition of claim 64, additionally comprising an antimicrobialselected from the group consisting of triclosan, copper (Cu), silver(Ag), nanosilver, gold (Au), selenium (Se), gallium (Ga),N-chlorotaurine, Listerine(R) compounds such as menthol, thymol, methylsalicylate, and eucalyptol.
 68. The composition of claim 64, wherein theprotamine comprises a protamine salt.
 69. The composition of claim 68,wherein the protamine salt is selected from the group consisting ofprotamine sulfate and protamine hydrochloride.
 70. The composition ofclaim 69, wherein the protamine salt comprises protamine sulfate.
 71. Apolymeric resin composition for manufacturing a medical device,comprising: a polymeric resin; and, an antimicrobial compositioncomprising: about 50 wt. % to about 99 wt. % of taurolidine; and, about1 wt. % to about 50 wt. % of protamine.
 72. The resin composition ofclaim 1, wherein the protamine comprises a protamine salt.
 73. The resincomposition of claim 72, wherein the protamine salt is selected from thegroup consisting of protamine sulfate and protamine hydrochloride. 74.The resin composition of claim 73, wherein the protamine salt comprisesprotamine sulfate.
 75. The medical device of claim 31, wherein thetissue repair fabric is selected from the group consisting of meshes,woven fabrics, nonwoven fabrics and tapes.
 76. The medical device ofclaim 32, wherein the polymer is selected from the group consisting ofpolyhydroxy acids, polyalkenes, polysilicones. fluorinated polyolefins,fibrin, and collagen.
 77. The medical device of claim 30, wherein thedevice is implantable.
 78. The method of claim 46, wherein the device isimplantable.
 79. The composition of claim 1, wherein the composition issuitable for implantation.
 80. The coating composition of claim 15,wherein the coating is suitable for application to an implantablemedical device.